1. Field of the Invention
The invention is related to a method which uses platelet contractile force (PCF) measurements and/or clot elastic modulus (CEM) as clinical markers to allow rapid assessment of a patient's risk of atherosclerosis or a patient's bleeding risk during surgical procedures.
2. Description of the Prior Art
The interplay between atherosclerosis and thrombosis is complex. Multiple local and systemic thrombotic risk factors have been shown to play a role in the destabilization of the vulnerable plaque and its clinical sequelae. Aside from local factors such as the degree of plaque erosion or stenosis, well known systemic risk factors include cholesterol, diabetes mellitus, tobacco, cocaine, hypertension, elevated fibrinogen, impaired fibrinolysis, activated platelets and products or by-products of the coagulation cascade.
Platelet activation occurs in the acute coronary syndrome1. The acute coronary syndrome is a continuum from unstable angina to non-Q and Q-wave myocardial infarction depending on the extent and duration of ischemia. Reduction in coronary blood flow occurs due to platelet aggregation, vasoconstriction at the site of coronary artery stenosis and endothelial injury. Endothelial injury may result from plaque ulceration, hemodynamic factors, systemic arterial hypertension, cardiac catherization, balloon angioplasty, etc. 2,3,4,5. It is critical to recognize the acute coronary syndrome in patients who present to an emergency department with chest pain in order to prevent inappropriate discharge and adverse consequences6,7.
Sensitive assays of individual components of the coagulation cascade have made laboratory evaluation of a biochemical hypercoagulable state possible. Prospective studies have suggested that elevated levels of factor VII, fibrinogen and other markers are associated with the development of ischemic cardiac events. However, traditional risk factors have not explained the increased cardiovascular risk in certain high risk groups such as diabetics. The contribution of platelet activation in patients presenting with an acute coronary syndrome has been well established. Unfortunately, to this point, tests of platelet function have not reflected changes predictive of a hypercoagulable state.
Platelet aggregometry, nuclear imaging techniques, serum markers such as Troponin I and T, P-selectin and E-selectin, intercellular adhesion molecules (ICAM) are some of the tools currently available and under investigation to identify patients with acute cardiac events. Nuclear imaging with technetium-99m sestamibi requires considerable resource utilization and has limited ability to differentiate between ischemia, ongoing infarction and prior infarction. Technetium-99m sestamibi also does not identify the unstable plaque 8,9,10. Elevations of troponin in patients who have myocardial infarction excluded predict an increased risk for short and long term adverse cardiac events. Their utility in acute events is limited since some degree of myocardial necrosis must occur prior to their release 11. Platelet aggregation may be a useful marker for predicting mortality in coronary events 12. However, aggregation techniques that have been used to evaluate platelet dysfunction have been limited to a few non-cardiac clinical situations 13. Measurement of P-selectin 13, ICAM-1 and/or E-selectin 14 as early markers of platelet activation is ill suited to an emergency department setting because the techniques of flow cytometry and ELISA are time consuming, require technical expertise and need substantial dedicated equipment. Newer methods to assess platelet function are needed.
The Hemodyne® Hemostasis Analyzer is an instrument which measures platelet activity (platelet contractile force, PCF) and clot strength (clot elastic modulus, CEM) in physical units of dynes & dynes/cm2 respectively15,16. U.S. Patents on which the Hemodyne® Hemostasis Analyzer is based include U.S. Pat. No. 4,986,964, U.S. Pat. No. 5,205,159, and U.S. Pat. No. 5,293,772, and each of these patents are incorporated by reference in their entirety. FIG. 1 schematically illustrates the components of a system similar to that described in these patents, and which is employed in the Hemodyne® Hemostasis Analyzer. A blood sample obtained from a patient is deposited in a sample cup 10 using a syringe 12 or other suitable device. The cup 10 is placed in a base 14, and a head piece 16 is inserted into the cup 10. This causes the blood 18 to distribute itself along the surface of the head piece 16 and up the sides of the cup 10. The force developed during contraction pulls the head piece 16 and base 14 closer together, and this force is measured using sensors connected to either or both the head piece 16 or base 14. To avoid adverse effects of the three dimensional structure on the clot during formation, a force can be periodically applied to the blood 18 during clotting by the head piece 16.
PCF and CEM are potentially useful tools in a variety of clinical situations17,18,19. PCF depends on thrombin production, platelet count, platelet viability and the degree of platelet inhibition15,20,21. CEM depends on the fibrinogen concentration, fibrin structure and platelet function15. Inhibition of fibrin(ogen) binding to GP IIb/IIIa blockade either by disruption of GP IIb/IIIa or by competitive blockade, inhibits platelet mediated force development and results in clot structures which are substantially less resistant to deformation by outside forces22.
Currently, a patient is screened for the presence of atherosclerosis by the patient's response to treadmill exercises and/or by cardiac catheterization. Both tests are time consuming and expensive, and catheterization is quite invasive to the patient. It would be helpful to have available a rapid, less invasive test which may identify those at risk for the presence of atherorsclerosis with the associated increased risk of adverse events such as myocardial infarction, peripheral vascular events, and stroke.